Abstract: A bacterial cell is much more than the sum of its parts. Most cellular functions are critically impacted not only by regulation of the genome and proteome, but also by the shape of the cell and how the shape dictates the localization of intracellular components. The ability to systematically manipulate cell shape will ultimately provide a powerful suite of applications in antibiotic drug development, synthetic biology, and biosensing. My laboratory will leverage insight from evolutionary, synthetic, and cell biological approaches to inform our ongoing development of quantitative, biophysical models of bacterial cell shape determination and growth. We have already successfully used modeling to predict the cell shape response to antibiotic treatment. We will focus our efforts on exploiting other predictions generated from quantitative models to reengineer cell shape and redesign the intracellular localization landscape. For the period of this award, three design targets will be pursued that leverage our expertise in biophysical modeling of cell shape to probe key features of cell growth: 1) We will explore the evolutionary origins of cell shape determination by transplanting foreign cytoskeletal elements between closely related bacteria. 2) We will program specific intracellular organizational phenotypes to dynamically reengineer cell shape. 3) We will determine the tension sensitivity of the growth machinery to elucidate potential feedback mechanisms for cell shape maintenance. These targets will strategically expand the experimental focus of my laboratory. Success will address many longstanding questions of how cells determine their shape and how they utilize shape to regulate complex intracellular processes such as cell division. The physical principles of organization are likely to appear in diverse biological contexts, in both bacterial cells and in higher organisms. Ultimately, we will challenge our understanding of cell shape determination by transforming shape into an experimentally tunable parameter. Public Health Relevance: Cell shape and intracellular organization have been recognized to play a critical role in a wide variety of important bacterial functions. We intend to systematically engineer cell shape to elucidate and exploit the links between shape, function, and fitness. Our work will produce tools for altering shape and organization with potential applications in biosensing, control of pathogenesis, and nanotechnology.